CD52 signaling via macrophage Siglec-G represents a therapeutic target for cancer immunotherapy.

Triple-negative breast cancer (TNBC) remains a lethal malignancy with limited targeted therapies and high metastatic rates. Cancer cells evade macrophage clearance by overexpressing anti-phagocytic cell surface proteins, termed "don't eat me" signals. Blocking antibodies (e.g., anti-CD47) against these signals show therapeutic promise in multiple cancers, yet variable responses and limited durability of efficacy to such agents imply additional unknown "don't eat me" signals exist. Here, we detected positive CD52 expression in tumors from TNBC patients and demonstrated that CD52 on TNBC cells facilitates immune evasion by engaging the inhibitory receptor sialic acid-binding Ig-like lectin G (Siglec-G) on tumor-associated macrophages. Genetic ablation of either CD52 or Siglec-G, as well as antibody-mediated blockade of their interaction restored macrophage phagocytic activity both in vitro and in vivo. This consequently suppressed tumor progression, improved survival, and promoted an immunologically active tumor microenvironment in TNBC mouse models. Additionally, cotreatment with anti-CD52 sensitized tumor cells to PD-1 blockade therapy in the spontaneous MMTV-PyMT TNBC model. Our findings identify CD52 as a prominently expressed anti-phagocytic checkpoint in TNBC and reveal the therapeutic potential of dual PD-1/CD52 blockade as a novel immunotherapeutic strategy.